The present invention relates to conjugates of sodium channel blockers, and particularly covalent conjugates comprising a pyrazinoylguanidine sodium channel blocker and another compound such as another pyrazinoylguanidine sodium channel blocker or a P2Y2 receptor agonist.
U.S. Pat. No. 4,501,729 to Boucher describes the use of respirable or non-respirable amiloride to hydrate airway mucous secretions, and U.S. Pat. No. 5,656,256 to Boucher and Stutts describes the use of respirable or non-respirable benzamil and phenamil to hydrate lung mucus secretions. U.S. Pat. No. 5,789,391 to Jacobus describes methods of treating sinusitis by administering uridine triphosphates (UTP) and related compounds such as P1,P4-di(uridine-5xe2x80x2 tetraphosphate (U2P4) in order to promote drainage of congested fluid in the sinuses.
U.S. Pat. No. 5,292,498 to Boucher describes nucleotides, particularly P2Y2 receptor agonists, that can be used to hydrate airway mucus secretions. Dinucleotides that can be used to hydrate airway mucus secretions are described in U.S. Pat. No. 5,635,160 to Stutts et al.. Additional compounds that are P2Y2 receptor ligands and can be used to hydrate airway mucus secretions are disclosed in W. Pendergast et al., U.S. Pat. No. 5,837,861, along with U.S. Pat. Nos. 5,763,447 to Jacobus and Leighton, and 5,789,391 to Jacobus et al.
A first aspect of the present invention is a compound (hereinafter also referred to as an xe2x80x9cactive compoundxe2x80x9d or xe2x80x9cactive agentxe2x80x9d) of the general formula P1-L-P2; wherein xe2x80x9cP1xe2x80x9d is a pyrazinoylguanidine sodium channel blocker, xe2x80x9cLxe2x80x9d is a linking group, and xe2x80x9cP2xe2x80x9d is either (i) a pyrazinoylguanidine sodium channel blocker or (ii) a P2Y2 receptor agonist. An advantage of compounds of the present invention is that they are substantially non-absorbable, or absorption-retardant or exhibit delayed absorption on mucosal (e.g., airway, gastrointestinal) surfaces, thereby contributing to a prolonged mode of action and fewer systemic side effects.
A second aspect of the present invention is a composition comprising an active compound as defined above in an effective therapeutic amount, in a pharmaceutically acceptable carrier.
A third aspect of the present invention is a method of treating a mucosal surface in a subject in need thereof, comprising administering an active compound as described herein in an amount effective to treat the subject. In general, treatment of the subject will mean that the mucosal surface being treated with a compound or composition of the present invention will be hydrated, or that the compound or composition being used will block or otherwise retard the absorption of liquid onto or onto the mucosal surface, or that the mucosal surface will otherwise exhibit an increased volume of liquid on the mucosal surface.
A fourth aspect of the present invention is the use of an active compound as described above for the preparation of a medicament for treating a mucosal surface in a subject in need thereof, as described herein.
The foregoing and other objects and aspects of the present invention are explained in detail in the specification set forth below.